The goal of this proposal is to conduct a phase Ib pharmacokinetic and pharmacodynamic trial of the novel biological response modifier (BRM) bryostatin 1 (bryo), a macrocyclic lactone activator of the enzyme protein kinase C (PKC) currently undergoing phase Ia evaluation. The rationale for this trial is provided by preclinical evidence indicating that chronic exposure of myeloid leukemia cells to bryo results in extensive dose- and schedule-dependent PKC down-regulation, dramatic potentiation of 1-beta-D-arabinofuranosylcytosine (ara-C)-induced apoptosis (programmed cell death), and highly synergistic antileukemic effects for the combination. Evidence also exists that bryo selectively enhances ara-C lethal effects in leukemic versus normal hematopoietic progenitors, leading to a net gain in therapeutic index for the combination. The central hypothesis upon which this proposal is based is that in vivo synergism between bryo and ara-C in humans will depend upon achievement of plasma bryo levels mimicking those demonstrated to be effective in preclinical studies (e.g., > 10 nM), or perhaps more importantly, capable of inducing substantial and sustained down- regulation of PKC activity in target tissues (e.g., leukemic blasts). Pursuit of these goals will be aided by two recent developments: (1) the availability of a highly sensitive platelet aggregation-based bryo bioassay capable of detecting plasma bryo concentrations in the nM range; and (2) the finding that bryo down-regulates total PKC activity in normal peripheral blood mononuclear cells (PBMNC) in a manner identical to that observed in human leukemia cells. A phase lb trial will be conducted in which patients will receive bryo according to three schedules: (a) a single dose administered as a one hour bolus i.v. infusion; (b) a single dose administered as a 24 hr continuous i.v. infusion; and (c) a one hour bolus i.v. infusion on day l and day 4. The goal of this study will be to identify a safe bryo dose and schedule capable of inducing equal to or greater than 90% down-regulation of PBMNC total PKC activity over an interval corresponding to the duration of a conventional high-dose ara-C (HIDAC) regimen (e.g., 72-144 hrs). Ancillary goals will be to define bryo pharmacokinetics when administered by these schedules, and to characterize toxic and therapeutic effects. Information obtained from this study will permit the rational design of successor phase I/II trials combining the BRM bryo with an appropriate HIDAC regimen in the treatment of AML and perhaps other hematological malignancies in humans.